Entry across a mucosal surface accounts for virtually all HIV-1 transmissions. However, many critical issues regarding the immunobiology of HIV-1 transmission in genital mucosa are poorly understood. Preliminary studies show that human vaginal dendritic cells (DCs) (a) consist of a significant proportion of myeloid cells, (b) are the first cells to take up HIV-1, (c) take up HIV-1 more effectively compared to MoDCs, (d) differentially take up virus with different glycan content or Env V1-V3 sequence, (e) disseminate HIV-1 locally and systemically, and (e) preferentially take up and transfer R5, rather than X4, virus to reporter cells. Accordingly, we hypothesize that vaginal DCs are a key mucosal gatekeeper that preferentially transmits T/F virus based on viral envelope (Env). Using human vaginal mucosal mononuclear cells and tissue explants, our specific aims seek to determine whether (1) human DCs preferentially take up transmitted/founder (T/F) virus, rather than chronic virus; (2) human DCs preferentially disseminate T/F virus, rather than chronic virus, into and through the mucosa to trans-infect mucosal and systemic lymphocytes; and (3) Env mediates preferential uptake and/or dissemination of T/F virus. Elucidating the role of human vaginal DCs in the selective acquisition and dissemination of T/F virus in mucosa will provide new insights into the early events in HIV-1 mucosal transmission and could inform the basic biology and ultimately prevention of HIV-1 transmission.